Genetic Neuro-Endocrine Role in Depression and Type 2 Diabetes. Depression confers a 60% increased risk for type 2 diabetes (T2D) and an increased risk for metabolic syndrome (MetS). The increased T2D risk in depressed patients is present independently from antidepressant therapy. Our central hypothesis is based on the idea that neuro-endocrine dysfunction in depression confers risk for T2D/MetS, and that common factors contribute to depression-T2D/MetS association. Stress plays a major role in depression. Under stress, the HPA axis releases corticotrophin releasing hormone (CRH) to stimulate via the CRH receptor (CRHR) adrenocorticotropin (ACTH) secretion from the anterior pituitary, leading to increased cortisol levels. Stress response dysregulation is associated with depression. Resistance of the CRH system in the brain, leading to hypercortisolism, may contribute to depression and T2D. Hypercortisolism and altered feedback inhibition are typical HPA abnormalities in depression, MetS and T2D. As depressed patients have significant hypercortisolism and inappropriately normal levels of plasma ACTH and cerebrospinal fluid CRH, considering their hypercortisolism and compared to control subjects, CRH and ACTH receptor dysfunctions are possible. Hypercortisolism increases glycogenolysis, gluconeogenesis, insulin resistance, free fatty acids, visceral obesity, blood pressure, and reduces insulin secretion, thereby contributing to MetS/T2D. Our specific objectives are to understand whether the HPA axis receptor genes associated with the stress response may contribute to the depression-MetS/T2D co-morbidity and/or to metabolic and psychological associated traits. The genes of interest are corticotropin-releasing hormone receptor genes (CRHR1 and CRHR2) and the melanocortin receptor genes (MC1R-MC5R). Specific Aim I: To determine the role of the HPA axis receptor genes (CRHR1, CRHR2, MC1R, MC2R, MC3R, MC4R, and MC5R) in T2D/MetS and associated traits within the Italian population; Specific Aim II: To determine the role of the same genes in depression and associated traits within the White USA families from the NIH repository. Significance: We challenge the accepted paradigm that T2D and MetS are only metabolic disorders, and that depression is purely a mental disorder, as they are all, at least partially and/or in a subgroup of patients, associated with hyperactivity of the neuro-endocrine cortisol pathway. Our study will lead to identify early on subjects at risk for depression and T2D/MetS and to prevent these disorders implementing lifestyle and behavioral-cognitive changes. Innovation: Performing linkage/association tests not only in a group of patients with T2D/MetS or depression, but also with the associated traits contributing to these diseases, is a powerful innovative strategy for gene identification. The linkage strategy will help identify rare variants as major disease players. The complex gene variants model, the multi- locus model and the gene imprinting model are innovative. We integrate human genetics and clinical phenotyping of disorders not usually studied jointly. We pioneer the joint study of the HPA axis receptors in T2D/MetS and depression in humans. These risk genes may multiply T2D/MetS and depression risk.